[go: up one dir, main page]

WO2000051624A2 - Methodes et compositions utiles a l'inhibition de l'apoptose - Google Patents

Methodes et compositions utiles a l'inhibition de l'apoptose Download PDF

Info

Publication number
WO2000051624A2
WO2000051624A2 PCT/US2000/006069 US0006069W WO0051624A2 WO 2000051624 A2 WO2000051624 A2 WO 2000051624A2 US 0006069 W US0006069 W US 0006069W WO 0051624 A2 WO0051624 A2 WO 0051624A2
Authority
WO
WIPO (PCT)
Prior art keywords
carbonyl
methylpropyl
oxadιazolyl
benzyloxycarbonyl
valyl
Prior art date
Application number
PCT/US2000/006069
Other languages
English (en)
Other versions
WO2000051624A3 (fr
Inventor
Leland Shapiro
Original Assignee
The Trustees Of University Technology Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Trustees Of University Technology Corporation filed Critical The Trustees Of University Technology Corporation
Priority to AU37314/00A priority Critical patent/AU3731400A/en
Publication of WO2000051624A2 publication Critical patent/WO2000051624A2/fr
Publication of WO2000051624A3 publication Critical patent/WO2000051624A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present mvention relates to compositions and methods useful in the inhibition of apoptosis Likewise, the present invention relates to methods of treating diseases associated with excessive or unregulated apoptosis
  • necrotic cell death is characterized by cytoplasmic swelling, rupturing of cellular membranes, inflammation and disintegration of subcellular and nuclear components
  • apoptosis is characterized by more organized changes in morphology and molecular structure
  • Apoptotic cells often condense and shrink, in part, by cytoplasmic membrane blebbmg, a process of shedding small packets of membrane-bound cytoplasm
  • the chromosomes of such cells condense around the nuclear periphery
  • m apoptotic cells the chromosomes are degraded by specific nucleases that cleave DNA to produce regular-sized fragments
  • the lamins are nuclear intermediate filament protems that form a fibrous layer between the inner nuclear membrane and the chromatin
  • the resulting lamma is thought to play a role in maintaining nuclear shape and m mediating chromatin- nuclear membrane interactions
  • the apoptosis-associated changes in nuclear shape might require lamin reorganization
  • Another polypeptide that is cleaved du ⁇ ng apoptosis is poly (ADP- ⁇ bose) polymerase (PARP)
  • PARP is an abundant nuclear enzyme that catalyzes the conversion of the dinucleotide NAD + to nicotinamide and protein-linked chains of ADP- ⁇ bose
  • PARP poly (ADP- ⁇ bose) polymerase
  • PARP is an abundant nuclear enzyme that catalyzes the conversion of the dinucleotide NAD + to nicotinamide and protein-linked chains of ADP- ⁇ bose
  • PITSLRE ⁇ 1 protein kinase adenomatous polyposis coh (APC) protem
  • APC adenomatous polyposis coh
  • retmoblastoma gene product adenomatous polyposis coh
  • nuclear matrix protems Cleavage of fod ⁇ n an abundant membrane associated cytoskeletal protem
  • PITSLRE ⁇ 1 protem kinase a member of the P34 cdc2 gene family has been shown to induce mitotic delay in CHO cells
  • PITSLRE ⁇ 1 protease is proteolytically cleaved du ⁇ ng FAS- or steroid- induced apoptosis in T-cells
  • Another major group of protease targets is the caspases, themselves proteases, or precursor forms
  • Increased levels or apparent induction of apoptosis is associated with a number of diseases including cancer, autoimmune diseases includmg rheumatoid arthritis, neurodegenerative diseases, myocardial infarction, stroke, sepsis, ischemia-reperfusion injury, toxin induced liver injury, and AIDS (see Kidd, V J , Annu Rev Physiol, 1998, 60, 533, List, P J M , et al , Artenoscler Thromb Vase Bwl 1999, 19, 14, Jabs, T , Bwchem Pharmacol 1999 57, 231, Deigner, H P , et al CurrMed Chem 1999, 6, 399)
  • the apoptosis appears to be mediated by oxygen free radicals [O ] which have been implicated in various disorders includmg atherosclerosis, diabetes, sepsis, Alzheimer's disease, arthritis, muscular dystrophy, cancer, Downs syndrome, multiple sclerosis, HIV infection and other inflammatory diseases (Mor
  • the present invention is directed to a method of treating an animal or a patient suffering from a disease characterized by excessive apoptosis.
  • the method of the invention comprises administering a therapeutically effective amount of at least one serine protease inhibitor and subsequently monitoring a decrease in apoptosis.
  • the animal is a human.
  • the agent is cci -antitrypsin (ATT) or an ⁇ i-antitrypsin-like agent.
  • peptides of interest are homologous and analogous peptides. All homologues are natural peptides which have sequence homology, analogs will be peptidyl derivatives, e.g., aldehyde or ketone derivatives of such peptides.
  • agents with o.]- antitrypsin-like activity are also envisioned.
  • peptide derivatives of c-i -antitrypsin compounds like oxydiazole, thiadiazole, CE-2072, UT-77, and triazole peptoids are preferred.
  • the cci -antitrypsin-like agent includes, but is not limited to, small organic molecules including naturally occu ⁇ ing, synthetic, and biosynthetic molecules, small inorganic molecules including naturally-occu ⁇ ing and synthetic molecules, natural products including those produced by plants and fungi, peptides, variants of cti-antitrypsin, chemically modified peptides, and proteins.
  • an individual with risk for a pathological disease or condition that is precipitated at least in part by excessive apoptosis can be treated to prevent the onset of acute disease with a prophylactic treatment of an agent exhibiting cci-antitrypsin or c-i -antitrypsin-like activity.
  • a further embodiment of the invention envisions a method for inhibiting apoptosis in an in vitro mammalian cell culture, an ex vivo mammalian tissue culture, or a mammalian organ, comprising providing to a cell culture, tissue culture, or organ, an amount of a serine protease inhibitor sufficient to inhibit apoptosis in the cell culture, tissue culture, or organ.
  • a measured amount of apoptosis is indicative of expression or activity of apoptosis.
  • a still further embodiment of the invention directed to a method of inhibiting apoptosis comprises allowing a serine protease inhibitor to bind to a protease and measuring the decrease in apoptosis.
  • Another embodiment of the invention is directed to a method of inhibiting apoptosis comprising allowing a serine protease inhibitor to bind to a cell surface receptor and measuring the decrease in apoptosis.
  • a yet still further embodiment of the invention is directed to use of oxidation-resistant and free- radical resistant inhibitors of serine proteases.
  • the oxidation-sensitive Met 358 in oti - antitrypsin can, by genetic engineering, be replaced by Val 358 - ⁇ ,-antitrypsin, which results in a molecule termed Val 358 - ⁇ -antitrypsin.
  • Val 358 - ⁇ , ⁇ -antitrypsin is a more potent inhibitor of neutrophil elastase than is Met 358 -o- ⁇ -antitrypsin possibly because of the stability of Val 358 - ⁇ j -antitrypsin to the neutrophil oxidative burst
  • the Met at position 358 is replaced with any hydrophobic or neutral oxidation-resistant ammo acid residue, including alamne, asparagine, ⁇ -amino butyric acid, anthranihc acid, ⁇ -cyanoalanine, ⁇ -(3,4-d ⁇ hyroxyphenyl) alamne, 3,5-dnodotyros ⁇ ne, glutamine, glycine, homose ⁇ ne, 3-hydroxyanthran ⁇ hc acid, 5 -hydroxy- ⁇ ndole-3 -acetic acid, 3-hydroxykynuren ⁇ ne, hydroxyproline, 5-hydroxy-tryptophan, indoleacetic acid,
  • FIG 1 illustrates the effect of O-i-antitrypsm on apoptosis in primary rat bram cerebral granule cells
  • FIG. 2 illustrates the effect of ⁇ j -antitrypsin and the peptoid CE-2072 on apoptosis in RCG Neuron (rat cerebral granule) cells, also termed RCGC
  • the current invention teaches methodologies and agents for treatmg animals and patients that suffer from a disease involving excessive apoptosis
  • the methods involve administration of therapeutically effective amounts of at least one serine protease inhibitor and testing for changes m apoptosis by any of several means known in the art
  • the se ⁇ ne proteases that are inhibited by the agent of the invention include trypsin, elastase, cathepsm G, tryptase TL-2, Factor Xa and protemase-3
  • the methods further involve inhibition of oxygen free radicals and inhibition of oxygen free radical formation by serine protease inhibitors
  • the method further includes a pharmaceutically acceptable carrier, any of which are known in the art.
  • Serine protease inhibitors include ⁇ i-antitrypsin, or
  • 0. 1 -antitrypsin-like agents In the latter group are included the oxydiazole, thiazole, triazole peptoids, or some combination of these agents.
  • the serine protease inhibitor is optionally derivatized chemically by esterification, acetylation or amidation.
  • a preferred embodiment of the invention is directed toward the treatment of myocardial infarction.
  • Another preferred embodiment of the invention is directed toward treatment of stroke, also known as brain ischemia or cerebrovascular accident.
  • the therapeutically effective amounts of the serine protease inhibitors are sufficient to bring the concentration of the added agent in the biological fluid of the individual to between about 10 pM and 2 mM.
  • the effective concentrations correspond to between about 5 nanograms per milliliter to about 10 milligrams per milliliter of the biological fluid of the individual.
  • the biological fluid of the individual is calculated from the total body weight of the individual or, in diseases that are localized to specific body compartments, from the volume of the compartment.
  • Biological fluid can include, but is not limited to, blood, plasma, serum, lymph, tears, saliva, cerebrospinal fluid, or combinations thereof.
  • the therapeutically effective amount is sufficient to bring the concentration in the biological fluid to between 0.5 ⁇ M and 200 ⁇ M, preferably between 5 ⁇ M and 200 ⁇ M, most preferably about 100 ⁇ M.
  • the agent is advantageously administered according to the weight of the subject.
  • Admimstration of the therapeutically effective amount of serine protease inhibitor can be in a bolus, for example, of about 0.001 to 7 g of oti -antitrypsin-like agent or about 1 to 70 g of ⁇ .] -antitrypsin, per kg of body weight of the subject.
  • Preferred amounts are about 0.01 g/kg body weight of oxydiazole, thiazole, or triazole peptoids, and about 1 g/kg body weight of natural or variant o-i -antitrypsin.
  • the administration of the agent in the invention can be performed parenterally, orally, vaginally, nasally, buccally, intravenously, intramuscularly, subcutaneously, rectally, intrathecally, epidurally, transdermally, intracerebroventricularly, or combinations thereof.
  • the agent is administered continuously or intermittently by osmotic pump or by implanted osmotic pump, including those of the Alza Corporation. It is a further embodiment of the invention that the therapeutically effective amount of the serine protease inhibitor is administered between about once daily to about once hourly. In a more preferred embodiment of the invention, the serine protease inhibitor is administered twice per day It is a further embodiment of the invention that the monitoring of changes m apoptosis be performed on tissue obtained from an animal or patient Any of several methods for monitoring apoptosis, well known in the art, are suitable
  • Apoptosis is associated with free radical production, including oxygen free radicals
  • Free radicals are known to inactivate natural ⁇ -ant ⁇ tryps ⁇ n Therefore, it is desirable to supplement ⁇ antitrypsm in blood with sufficient ⁇ -ant ⁇ tryps ⁇ n-l ⁇ ke activity which is not inactivated by free radicals
  • a mutant o-i-antitrypsm resistant to inactivation by free radicals, or administration of a synthetic molecule that is not inactivated by free radicals is contemplated
  • co-administration of a free radical scavenger or inhibitor is contemplated
  • the present invention is not limited by the mechanism of action of o-i - antitrypsin inhibitors in decreasmg apoptosis
  • the apoptosis may be mediated by tumor necrosis factor, by anti-Fas or by any other mechanism
  • apoptosis not mediated by tumor necrosis factor is inhibited by the ⁇ i - antitryp
  • Yet another embodiment of the invention is directed toward the inhibition of apoptosis resulting from the interaction between a serme protease inhibitor and a cell surface receptor and resulting in a measurable decrease m apoptosis
  • the serine protease inhibitor of this embodiment is an ⁇ j - antitrypsin or an ⁇ . - antitrypsin-like agent
  • the oci - antitrypsm-hke agents mcludes substituted oxydiazoles, substituted thiadiazole, substituted triazole peptoids, or combinations of these agents
  • the substituted oxydiazole, thiadiazole, and triazole peptoids are synthesized de novo or de ⁇ vatized from existing compounds
  • the diseases include cancer, neurodegenerative diseases, myocardial infarction, and stroke
  • the cancers include bladder, breast, kidney, leukemia, lung, myoloma, posarcoma, lymphoma, tongue, prostate, and uterine cancers
  • the method of the invention is also applied to Alzheimer's disease, arthritis, muscular dystrophy, Downs Syndrome, sepsis, HIV infection, multiple sclerosis, arteriosclerosis, diabetes, and arthritis
  • the mvention is applied to any disease associated with elevated levels of apoptosis
  • the agents are delivered by any of a variety of routes includmg by injection (e g , subcutaneous, intramuscular, intravenous, mtra-arte ⁇ al, and mtrape ⁇ toneal), by contmuous intravenous infusion, transdermally, orally (e g , tablet, pill, liquid medicine), by implanted osmotic pumps (e g , ALZA Corp ), by suppository or aerosol spray
  • routes includedmg by injection (e g , subcutaneous, intramuscular, intravenous, mtra-arte ⁇ al, and mtrape ⁇ toneal), by contmuous intravenous infusion, transdermally, orally (e g , tablet, pill, liquid medicine), by implanted osmotic pumps (e g , ALZA Corp ), by suppository or aerosol spray
  • routes include injection (e g , subcutaneous, intramuscular, intravenous, mtra-arte ⁇ al, and mtrape ⁇ toneal
  • the compounds of the present invention are used as therapeutic agents in the treatment of a physiological, or especially, pathological, condition caused in whole or part by uncontrolled serine protease and apoptosis activity.
  • the peptides or peptoids can be administered as free peptides, free peptoids, or pharmaceutically acceptable salts thereof.
  • the terms used herein conform to those in Budavari, S. (Ed.), "The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals," Merck Company, Inc., twelfth edition.
  • pharmaceutically acceptable salt refers to those acid addition salts or methyl complexes of the peptides which do not significantly or adversely affect the therapeutic properties including efficacy and toxicity, of the peptides and peptoids.
  • the peptides and peptoids are administered to individuals as a pharmaceutical composition which, in most cases, will comprise the peptide, peptoid, and/or pharmaceutical salts thereof with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to those solid and liquid carriers, which do not significantly or adversely affect the therapeutic properties of the peptides.
  • compositions containing peptides and/or peptoids of the present invention are administered to individuals, particularly humans, either intravenously, subcutaneously, intramuscularly, intranasally, orally, topically, transdermally, parenterally, gastrointestinally, transbronchially, and transalveolarly.
  • Topical administration is accomplished by a topically applied cream, gel, rinse, etc. containing therapeutically effective amounts of inhibitors of serine proteases.
  • Transdermal admimstration is accomplished by administration of a cream, rinse, gel, etc. capable of allowing the inhibitors of serine proteases to penetrate the skin and enter the blood stream.
  • Parenteral routes of admimstration include, but are not limited to, direct injection such as intravenous, intramuscular, intraperitoneal, or subcutaneous injection.
  • Gastrointestinal routes of admimstration include, but are not limited to, ingestion and rectal.
  • Transbroncheal and transalveolar routes of administration include, but are not limited to, inhalation, either via the mouth or intranasally, and direct injection into an area, such as through a tracheotomy, endotracheal tube, or aspirated through a respiratory mist.
  • osmotic pumps are used for administration. The necessary dosage will vary with the particular condition being treated, method of administration, and rate of clearance of the molecule from the body. 6.
  • Rats female, 250-300g each are randomly assigned to one of four groups myocardial infarction control, stroke control, myocardial infarction, and stroke
  • the rats are subjected to a 30 minute hgation of the coronary arterial supply (for the myocardial infarction group) or the left carotid artery (for the stroke group), followed by release of the ligature Sham operated controls receive the cut-down and manipulation of the artery but without hgation
  • half of the animals in each group receive c -antitrypsin (sufficient to achieve a 50 ⁇ M concentration of added agent in the blood, or in the alternative, an amount equal to 10 mg/kg body weight) and the other half receive a body-weight equivalent volume of AAT vehicle, intravenously
  • the AAT vehicle is phosphate-buffered salme, or optionally, any pharmaceutically acceptable earner At twenty-four hours after release of the sham or actual hg
  • one preferred embodiment of the process is the co-administration of ⁇ , -antitrypsin and a free radical scavenger, such as glutathione (1 mg/kg body weight).
  • a free radical scavenger such as glutathione (1 mg/kg body weight).
  • oxidation-resistant o-i -antitrypsin variants are used to avoid inactivation by excess free radicals.
  • synthetic ⁇ i-antitrypsin or recombinant ⁇ ,]- antitrypsin produced with alternative and oxidation-resistant amino acid sequences are embodiments of the invention.
  • RCG neuronal cells are seeded into cell culture dishes in 400 ⁇ l cell culture medium (Eagle's basal medium, BME) containing 10% (v/v) FBS. At day two the now conditioned medium is removed and the cells are treated for 10 hours as follows:
  • agent CE-2072 a synthetic inhibitor of serine protease.
  • the latter is formally known as benzyloxcarbonyl-L-valyl-N-[l-(2-[5-(3-methylbenzyl)-l,3,4-oxadiazolyl] carbonyl)-2-(S)- Methylpropyl]-L-prolinamide.
  • TRANSPORT AND TRANSPLANT Human donor organs are subject to ischemia during transport, which can last up to several hours.
  • Biopsies (3mm) are removed from the top medial surface of donor kidneys undergoing transport prior to implantation, and grouped by time after removal from the donor: 1-2 hours, 2-4 hours, and greater than 4 hours.
  • Donor kidneys transplanted within one hour serve as the first control and the contralateral kidney serves as the second control.
  • Half of the donor kidneys are treated with ⁇ i-antitrypsin (10 mg/ml fluid) upon removal from the donor to inhibit apoptosis.
  • Val 358 -antitrypsin and Ile 358 -antitrypsin are produced from the appropriate nucleotide sequences by methods well known in the art, including construction of a plasmid, transfection of the host E. coli. selection of transfected colonies, expansion of the culture, and isolation and purification of the mutant gene product. Amounts of the recombinant agents effective in inhibiting apoptosis, excessive clotting, neutrophil extravasation, ischemia-reperfusion injury, or myocardial damage are applied in an experimental model of myocardial infarction (see Example 6.1, supra). Effective amounts are between 0.03 and 7 g/kg body weight, for example, about 0.5 g/kg. In some experiments the amount of variant antitrypsin is measured in the blood or other biological fluid. In those tests sufficient variant antitrypsin is admimstered to provide a concentration of about 1 ⁇ M to about 100 ⁇ M in the blood or biological fluid.
  • ⁇ -i- antitrypsin 3.0 mg/ml
  • ⁇ -i-antitrypsin 3.0 mg/ml
  • replacement of the cell culture medium with either control medium containing 10% (vol/vol) fetal bovine serum, medium devoid of fetal bovine serum, or medium devoid of fetal bovine serum but containing ⁇ j -antitrypsin.
  • control medium containing 10% (vol/vol) fetal bovine serum, medium devoid of fetal bovine serum, or medium devoid of fetal bovine serum but containing ⁇ j -antitrypsin.
  • ⁇ j -Antitrypsin completely reverses the apoptosis associated with serum depletion, which results in cell death.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Dermatology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Oncology (AREA)
  • Vascular Medicine (AREA)
  • Communicable Diseases (AREA)

Abstract

L'invention concerne une méthode de traitement d'un animal qui souffre d'une maladie caractérisée par un excès d'apoptose en administrant dans une optique thérapeutique une quantité efficace d'au moins un inhibiteur de sérine protéase, et en surveillant une baisse de l'apoptose en résultant. L'inhibiteur de cette invention comprend α1-antitrypsine ou un agent similaire à α1-antitrypsine, y compris, mais non de manière exclusive, des variants résistants à l'oxydation de α1-antitrypsine et des peptides à activité antitrypsine. Les maladies qui peuvent être traitées par la méthode de cette invention comprennent le cancer, les maladies auto-immunes, les maladies neurodégénératives causées par une sepsie, les infarctus du myocarde, les attaques, les lésions de reperfusion d'ischémie, les atteintes hépatiques provoquées par une toxine et le SIDA. Cette méthode est également appropriée à la prévention ou à l'amélioration des maladies caractérisées par un excès d'apoptose.
PCT/US2000/006069 1999-03-05 2000-03-03 Methodes et compositions utiles a l'inhibition de l'apoptose WO2000051624A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37314/00A AU3731400A (en) 1999-03-05 2000-03-03 Methods and compositions useful in inhibiting apoptosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12316799P 1999-03-05 1999-03-05
US60/123,167 1999-03-05

Publications (2)

Publication Number Publication Date
WO2000051624A2 true WO2000051624A2 (fr) 2000-09-08
WO2000051624A3 WO2000051624A3 (fr) 2000-12-28

Family

ID=22407091

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/006069 WO2000051624A2 (fr) 1999-03-05 2000-03-03 Methodes et compositions utiles a l'inhibition de l'apoptose

Country Status (3)

Country Link
US (4) US7704958B1 (fr)
AU (1) AU3731400A (fr)
WO (1) WO2000051624A2 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10148553A1 (de) * 2001-10-01 2003-04-17 Protagen Ag Proteinaseinhibitoren zur Therapie und Diagnose von neurodegenerativen Krankheiten
US6670325B2 (en) 2001-10-19 2003-12-30 Alpha Med Pharmaceuticals Corp. Treatment of osteocarcinoma with alpha-1—antitrypsin or secretory leucocyte protease inhibitor
WO2003060466A3 (fr) * 2001-12-21 2004-02-12 Immunochemistry Technologies L Marquage d'affinite des serines proteases dans la detection simultanee de plusieurs taux d'activite des serines proteases
WO2005112989A1 (fr) * 2004-05-19 2005-12-01 Imperial College Innovations Limited Inhibiteurs de proteases et leurs applications therapeutiques
WO2006133403A3 (fr) * 2005-06-07 2007-05-03 Univ Colorado Inhibiteurs de l'activite serine protease et leur utilisation dans des procedes et compositions pour le traitement du rejet du greffon et la promotion de la survie du greffon
EP1697331A4 (fr) * 2003-12-19 2010-08-04 Merck Sharp & Dohme Inhibiteurs de kinesines mitotiques
US7850970B2 (en) 2003-08-26 2010-12-14 The Regents Of The University Of Colorado Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
US20110237496A1 (en) * 2008-09-10 2011-09-29 Ilana Nathan Antinecrotic activity of alpha 1-antitrypsin
US8034766B2 (en) 2006-10-27 2011-10-11 E I Du Pont De Nemours And Company Compositions and methods for prion decontamination
US20130195859A1 (en) * 2010-03-04 2013-08-01 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods for modulating cardiac conditions
US9457070B2 (en) 2005-06-07 2016-10-04 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses of alpha 1-antitrypsin for early intervention in bone marrow transplantation and treatment of graft versus host disease
CN107847550A (zh) * 2015-04-16 2018-03-27 首创生物药品发展有限公司 用于脑血管疾病的治疗肽
US9938353B2 (en) 2011-06-24 2018-04-10 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses for alpha-1 antitrypsin fusion molecules
US10478508B2 (en) 2012-01-10 2019-11-19 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses for alpha-1 antitrypsin fusion molecules
JP2020063311A (ja) * 2020-01-31 2020-04-23 プライム・バイオ‐ドラッグ・ディヴェロップメント・リミテッドＰｒｉｍｅ Ｂｉｏ‐Ｄｒｕｇ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 脳血管疾患用治療ペプチド

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3864000A (en) * 1999-03-05 2000-09-21 Trustees Of University Technology Corporation, The Inhibitors of serine protease activity, methods and compositions for treatment of herpes viruses
WO2000051624A2 (fr) * 1999-03-05 2000-09-08 The Trustees Of University Technology Corporation Methodes et compositions utiles a l'inhibition de l'apoptose
US20090227518A1 (en) * 2005-12-02 2009-09-10 The Regents Of The University Of Colorado Compositions and methods for treating actin-mediated medical conditions
WO2008033890A2 (fr) * 2006-09-12 2008-03-20 Beth Israel Deaconess Medical Center, Inc. Compositions contenant de l'alpha-1-antitrypsine et leurs procédés d'utilisation
ES2611944T3 (es) * 2007-11-02 2017-05-11 Grifols Therapeutics Inc. Procedimiento, composición y artículo de fabricación para proporcionar alfa-1-antitripsina
EP2496246B1 (fr) 2009-11-03 2018-06-27 Grifols Therapeutics LLC Composition, procédé et kit pour inhibiteur d'alpha-1 protéinase
CA2792837A1 (fr) * 2010-03-17 2011-09-22 Arbonne International Llc Supplement oral
WO2011156820A2 (fr) * 2010-06-11 2011-12-15 The Regents Of The University Of Colorado, A Body Corporate Compositions, méthodes et utilisations pour le traitement du diabète insulino-dépendant
EP2611459B1 (fr) 2010-08-31 2019-12-11 Yissum Research Development Company of the Hebrew University of Jerusalem, Ltd. Polypeptides dérivés d'alpha-1 antitrypsin pour l'utilisation dans le traitement de l'inflammation
US9518107B2 (en) 2010-08-31 2016-12-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. Pharmaceutical compositions containing polypeptides derived from α-1 antitrypsin and methods of use thereof
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
CN105431165A (zh) 2013-05-15 2016-03-23 莫尔研究应用有限公司 用于治疗心肺手术后的术后并发症的组合物和方法
WO2016046822A1 (fr) 2014-09-22 2016-03-31 Hadasit Medical Research Services And Development Ltd. Alpha-1 anti-trypsine pour le traitement de maladies hépatiques
WO2018183705A1 (fr) 2017-03-29 2018-10-04 Cornell University Thérapie génique à aat résistant à l'oxydation

Family Cites Families (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5874424A (en) 1995-12-20 1999-02-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6342373B1 (en) * 1983-11-21 2002-01-29 Ucp Gen-Pharma Ag Process for preparing recombinant eglin, protease inhibitor
US4711848A (en) * 1984-03-14 1987-12-08 Zymogenetics, Inc. Site specific mutagenesis in alpha-1-antitrypsin
US5247084A (en) 1985-11-12 1993-09-21 Ono Pharmaceutical Co., Ltd. Derivatives of p-guanidinobenzoic acid
US4629567A (en) * 1986-03-07 1986-12-16 Smithkline-Rit Alpha-1-antiprotease purification
US5322775A (en) 1986-06-30 1994-06-21 Pharmaceutical Proteins Ltd. Peptide production
US5508031A (en) * 1986-11-21 1996-04-16 Cetus Oncology Corporation Method for treating biological damage using a free-radial scavenger and interleukin-2
US5093316A (en) * 1986-12-24 1992-03-03 John Lezdey Treatment of inflammation
US4829054A (en) * 1987-04-13 1989-05-09 Miles Laboratories, Inc. Method of decreasing lung damage in a host following the onset of gram negative septicemia/endotoxemia
GB8826446D0 (en) 1988-11-11 1988-12-14 Agricultural & Food Res Peptide production
US5665589A (en) 1988-12-14 1997-09-09 The United States Of America As Represented By The Department Of Health And Human Services Human liver epithelial cell lines
US5529920A (en) 1988-12-14 1996-06-25 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Human liver epithelial cell line and culture media therefor
US5399346A (en) 1989-06-14 1995-03-21 The United States Of America As Represented By The Department Of Health And Human Services Gene therapy
US5612194A (en) 1989-06-23 1997-03-18 Trustees Of The University Of Pennsylvania Methods of producing effective recombinant serine protease inhibitors and uses of these inhibitors
US5040545A (en) * 1989-11-02 1991-08-20 Possis Medical, Inc. Releasable lock assembly
US5663416A (en) 1990-05-22 1997-09-02 Cortech Inc. Oxidant sensitive and insensitive aromatic esters as inhibitors of human neutrophil elastase
US5187089A (en) * 1990-06-21 1993-02-16 Incyte Pharmaceuticals, Inc. Protease nexin-i variants which inhibit elastase
US5134119A (en) * 1990-10-16 1992-07-28 Lezdey John Treatment of inflammation using 358 substituted alpha-antitrypsin
US5240956A (en) 1990-11-07 1993-08-31 Cortech, Inc. Ester inhibitors
US5470970A (en) 1991-02-28 1995-11-28 Dana-Farber Cancer Institute, Inc. Maspin, a serpin with tumor suppresing activity
US5610140A (en) 1991-04-01 1997-03-11 Cortech, Inc. Bradykinin receptor antagonists with neurokinin receptor blocking activity
US5843900A (en) 1991-04-01 1998-12-01 Cortech, Inc. Bradykinin antagonists
CZ203693A3 (en) 1991-04-01 1994-07-13 Cortech Bradykinin antagonists
US5863899A (en) 1991-04-01 1999-01-26 Cortech, Inc. Bradykinin antagonists
US5416191A (en) 1991-04-01 1995-05-16 Cortech, Inc. Bradykinin antagonists
WO1992018141A1 (fr) 1991-04-18 1992-10-29 The Uab Research Foundation Compositions et procedes d'inhibition de l'elastase
US5478727A (en) 1991-05-24 1995-12-26 Arch Development Corporation Methods and compositions for the preparation and use of a herpes protease
FR2679920A1 (fr) 1991-08-02 1993-02-05 Rhone Poulenc Rorer Sa Levures recombinantes hautement stables pour la production de proteines recombinantes, leur preparation et leur utilisation.
US5641670A (en) 1991-11-05 1997-06-24 Transkaryotic Therapies, Inc. Protein production and protein delivery
US5216022A (en) 1991-12-19 1993-06-01 Cortech, Inc. Aromatic esters of phenylenedialkanoates as inhibitors of human neutrophil elastase
WO1993018794A1 (fr) * 1992-03-26 1993-09-30 Gensia, Inc. Therapie in vivo recourant a des peptides
GB9209882D0 (en) * 1992-05-07 1992-06-24 Glaxo Lab Sa Compositions
JP2736952B2 (ja) 1992-09-18 1998-04-08 小野薬品工業株式会社 アミジノフェノール誘導体およびその誘導体を有効成分として含有する薬剤
US5376633A (en) 1992-09-30 1994-12-27 Lezdey; John Method for deactivating viruses in blood component containers
EP0677099B1 (fr) 1992-12-31 2005-11-30 Dana-Farber Cancer Institute, Inc. Sequence amplificatrice modulant l'expression dans les cellules epitheliales
US5604201A (en) 1993-01-08 1997-02-18 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University, A Non-Profit Organization Methods and reagents for inhibiting furin endoprotease
EP0701570B1 (fr) 1993-05-18 2001-12-19 Korea Institute Of Science And Technology Muteine thermoresistante d'alpha-1-antitrypsine
US5750506A (en) 1993-06-18 1998-05-12 Cortech, Inc. Bradykinin antagonists with extended hydrophobic side chains
US5346886A (en) * 1993-11-15 1994-09-13 John Lezdey Topical α-1-antitrypsin, non-aqueous lipid miscible, benzalkonium chloride compositions for treating skin
US5759548A (en) 1993-11-30 1998-06-02 Lxr Biotechnology Inc. Compositions which inhibit apoptosis, methods of purifying the compositions and uses thereof
CA2137106C (fr) 1993-12-03 2000-02-08 Hisao Nakai Derives d'amidinophenol
WO1995024422A1 (fr) 1994-03-09 1995-09-14 Cortech, Inc. Peptides antagonistes de la bradykinine contenant des glycines substituees en n
KR100366328B1 (ko) * 1994-06-02 2003-03-06 메렐 파마슈티칼스 인크. 엘라스타제의퍼플루오로알킬케톤억제제및이들의제조방법
US6090786A (en) 1994-06-10 2000-07-18 Fondatech Benelux N.V. Serine proteases, their activity and their synthetic inhibitors
US5486470A (en) 1994-07-21 1996-01-23 Merck & Co., Inc. Purified herpes simplex virus protease and methods of purification
US5610285A (en) 1994-08-24 1997-03-11 Bayer Corporation Purification of α-1 proteinase inhibitor using novel chromatographic separation conditions
US5652237A (en) * 1994-09-09 1997-07-29 Warner-Lambert Company 2-substituted-4H-3, 1-benzoxazin-4-ones and benzthiazin-4-ones as inhibitors of complement C1r protease for the treatment of inflammatory processes
US5514653A (en) 1994-09-09 1996-05-07 Washington University Method of blocking the SEC receptor
SK37997A3 (en) * 1994-09-23 1998-12-02 Arris Pharm Corp Compositions and methods for treating mast-cell inflammatory condition
DK0788546T3 (da) 1994-10-18 2007-04-10 Dendreon Corp Nematode-ekstraherede serinproteaseinhibitorer og antikoagulerende proteiner
US5498616A (en) 1994-11-04 1996-03-12 Cephalon, Inc. Cysteine protease and serine protease inhibitors
US5618792A (en) 1994-11-21 1997-04-08 Cortech, Inc. Substituted heterocyclic compounds useful as inhibitors of (serine proteases) human neutrophil elastase
US5780009A (en) 1995-01-20 1998-07-14 Nexia Biotechnologies, Inc. Direct gene transfer into the ruminant mammary gland
US5712117A (en) 1995-02-08 1998-01-27 Zymogenetics, Inc. Cytoplasmic antiproteinase-2 and coding sequences
US5798442A (en) 1995-04-21 1998-08-25 Merck Frosst Canada, Inc. Peptidyl derivatives as inhibitors of pro-apoptotic cysteine proteinases
US6255091B1 (en) 1995-04-28 2001-07-03 Axys Pharmaceuticals, Inc. Potentiating metal mediated serine protease inhibitors with cobalt or zinc ions
US6126933A (en) * 1995-06-27 2000-10-03 Genetics Institute Methods of treating inflammatory bowel diseases by administering IL-11
JPH11509231A (ja) 1995-07-17 1999-08-17 セフアロン・インコーポレーテツド リン−含有システイン及びセリンプロテアーゼ阻害剤
US5849863A (en) 1995-09-08 1998-12-15 University Of Colorado Cytolytic bradykinin antagonists
US5834431A (en) 1995-09-08 1998-11-10 Cortech, Inc. Des-Arg9 -BK antagonists
US5811241A (en) 1995-09-13 1998-09-22 Cortech, Inc. Method for preparing and identifying N-substitued 1,4-piperazines and N-substituted 1,4-piperazinediones
AU6977096A (en) 1995-09-14 1997-04-01 Cephalon, Inc. Ketomethylene group-containing cysteine and serine protease inhibitors
JP2002515860A (ja) 1995-11-28 2002-05-28 セフアロン・インコーポレーテツド システイン及びセリンプロテアーゼのｄ―アミノ酸由来のインヒビター
WO1997024339A1 (fr) 1995-12-27 1997-07-10 Ono Pharmaceutical Co., Ltd. Derives de tetrazole et medicaments les contenant a titre d'ingredients actifs
IL120310A (en) 1996-03-01 2002-02-10 Akzo Nobel Nv Serine protease inhibitors and pharmaceuticals containing them
DE69735996T2 (de) 1996-03-11 2007-02-15 Bayer Corp. Menschlicher bikunin
KR20000005312A (ko) 1996-04-10 2000-01-25 오노 야꾸힝 고교 가부시키가이샤 트립타아제 억제제 및 신규 구아니디노 유도체
AU2792097A (en) 1996-05-24 1998-01-05 Ono Pharmaceutical Co. Ltd. Phenylsulfonamide derivatives
US5780440A (en) * 1996-06-17 1998-07-14 Protease Sciences Inc. Treatment of pulmonary disease with protease inhibitors
AU3232597A (en) 1996-06-18 1998-01-07 Warner-Lambert Company Pyrrolo{1,2-a}pyrazine-1,4-dione serine protease inhibitors
WO1997049679A1 (fr) 1996-06-27 1997-12-31 Ono Pharmaceutical Co., Ltd. Derives d'aryle (sulfure, oxyde sulfonique et sulfone) et medicaments les contenant en tant que principe actif
US5616693A (en) 1996-07-01 1997-04-01 Alpha Therapeutic Corporation Process for seperating alpha-1-proteinase inhibitor from COHN IV1 +1V4 paste
US5872124A (en) * 1996-07-31 1999-02-16 Thomas Jefferson University Treatment of diseases of the central nervous system using uric acid as a scavenger of peroxynitrite
JP2002515878A (ja) 1996-08-16 2002-05-28 コーテック インコーポレーテッド 脳虚血性損傷およびその他の神経の病気を治療する方法
KR100318619B1 (ko) 1996-08-29 2002-02-19 아끼구사 나오유끼 설비고장진단방법과그장치및고장진단기능을가진반도체제조장치
WO1998016630A1 (fr) * 1996-10-11 1998-04-23 The Texas A & M University System Techniques permettant la production de cellules sexuelles primordiales et d'especes animales transgeniques
US6372887B1 (en) 1996-11-07 2002-04-16 Heska Corporation Flea serine protease inhibitor proteins
US5928883A (en) * 1996-11-13 1999-07-27 Mayo Foundation For Medical Education Eosinophil granole proteins as indicators of inflammatory bowel disorders
JP2002514192A (ja) 1996-11-13 2002-05-14 セフアロン・インコーポレーテツド ベンゾチアゾおよび関連の複素環基を含有するシステインおよびセリンプロテアーゼ阻害剤
US6180402B1 (en) 1996-11-20 2001-01-30 Qlt Inc. Method for inhibiting apoptosis induced by photodynamic therapy using a cysteine or serine protease inhibitor
TW499412B (en) 1996-11-26 2002-08-21 Dimensional Pharm Inc Aminoguanidines and alkoxyguanidines as protease inhibitors
NZ336046A (en) 1996-12-06 2000-10-27 Cortech Inc Serine protease inhibitors containing substituted oxadiazole, thiadiazole and triazole peptide derivatives
US5851987A (en) * 1997-04-14 1998-12-22 Incyte Pharmaceuticals, Inc. Human tumor-associated Kazal inhibitor-like polypeptides and encoding polynucleotides
WO1998046597A1 (fr) 1997-04-14 1998-10-22 Emory University Inhibiteurs de serines proteases
US6004933A (en) 1997-04-25 1999-12-21 Cortech Inc. Cysteine protease inhibitors
CA2287569A1 (fr) 1997-05-02 1998-11-12 Akzo Nobel Nv Inhibiteurs de la serine protease
IL132630A0 (en) 1997-05-08 2001-03-19 Smithkline Beecham Corp Protease inhibitors
US5908861A (en) * 1997-05-13 1999-06-01 Octamer, Inc. Methods for treating inflammation and inflammatory disease using pADPRT inhibitors
AT407114B (de) 1997-06-10 2000-12-27 Immuno Ag Alpha 1-antitrypsin-präparation sowie verfahren zu deren herstellung
US6124257A (en) * 1997-08-28 2000-09-26 Lezdey; John Method of treatment
AU2300699A (en) 1998-02-17 1999-08-30 Ono Pharmaceutical Co. Ltd. Amidino derivatives and drugs containing the same as the active ingredient
WO1999043308A2 (fr) 1998-02-27 1999-09-02 Marlene Rabinovitch Traitement de l'hypertension arterielle pulmonaire par suppression de la tenascine et inhibition de l'elastase
US6323219B1 (en) * 1998-04-02 2001-11-27 Ortho-Mcneil Pharmaceutical, Inc. Methods for treating immunomediated inflammatory disorders
DE19828113A1 (de) * 1998-06-24 2000-01-05 Probiodrug Ges Fuer Arzneim Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV
JP2002524424A (ja) * 1998-09-08 2002-08-06 モンサント カンパニー 誘導性一酸化窒素シンターゼ阻害剤を用い変形性関節症を治療する方法
CA2383486A1 (fr) * 1999-02-01 2000-08-03 Darren Lezdey Traitement de la mastocytose gastro-intestinale et de la vessie
AU3864000A (en) * 1999-03-05 2000-09-21 Trustees Of University Technology Corporation, The Inhibitors of serine protease activity, methods and compositions for treatment of herpes viruses
WO2000052034A2 (fr) 1999-03-05 2000-09-08 The Trustees Of University Technology Corporation Inhibiteurs d'activite de serine protease, methodes et compositions de traitement d'infections virales
WO2000051624A2 (fr) * 1999-03-05 2000-09-08 The Trustees Of University Technology Corporation Methodes et compositions utiles a l'inhibition de l'apoptose
US6849605B1 (en) * 1999-03-05 2005-02-01 The Trustees Of University Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of viral infections
AU3511500A (en) * 1999-03-05 2000-09-21 Trustees Of University Technology Corporation, The Inhibitors of serine protease activity, methods and compositions for treatment of nitric oxide-induced clinical conditions
US6110949A (en) * 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
ES2264937T3 (es) * 1999-07-30 2007-02-01 Boehringer Ingelheim Pharmaceuticals Inc. Nuevos compuestos derivados de succinato, utiles como inhibidores de cisteina-proteasa.
US6420364B1 (en) * 1999-09-13 2002-07-16 Boehringer Ingelheim Pharmaceuticals, Inc. Compound useful as reversible inhibitors of cysteine proteases
US20040220242A1 (en) * 2003-05-02 2004-11-04 Leland Shapiro Inhibitors of serine protease activity, methods and compositions for treatment of nitric oxide induced clinical conditions
CA2536918A1 (fr) * 2003-08-26 2005-03-03 Leland Shapiro Compositions et procedes pour molecules de fusion fc de l'alpha-1 antitrypsine
US20090118162A1 (en) * 2005-06-07 2009-05-07 Regents Of The University Of Colorado Inhibitors of serine protease activity and their use in methods and compositions for treatment of graft rejection and promotion of graft survival
WO2009005877A2 (fr) * 2007-04-20 2009-01-08 Regents Of The University Of Colorado Compositions et procédés d'utilisation d'une antitrypsine alpha-1 n'ayant pas d'activité inhibitrice de sérine protéase significative
US8715649B2 (en) * 2005-06-07 2014-05-06 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods of use for alpha-1 antitrypsin having no significant serine protease inhibitor activity
EP2066662B1 (fr) * 2006-09-21 2012-12-05 Kyorin Pharmaceutical Co., Ltd. Inhibiteurs de serine hydrolase
US20110201587A1 (en) * 2010-02-16 2011-08-18 Bio Holding, Inc. Hsp90 inhibitors and methods of use
WO2011156820A2 (fr) * 2010-06-11 2011-12-15 The Regents Of The University Of Colorado, A Body Corporate Compositions, méthodes et utilisations pour le traitement du diabète insulino-dépendant

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028621A3 (fr) * 2001-10-01 2003-10-09 Protagen Ag Inhibiteurs de proteinase utilises dans le traitement et le diagnostic de maladies neurodegeneratives
DE10148553A1 (de) * 2001-10-01 2003-04-17 Protagen Ag Proteinaseinhibitoren zur Therapie und Diagnose von neurodegenerativen Krankheiten
US6670325B2 (en) 2001-10-19 2003-12-30 Alpha Med Pharmaceuticals Corp. Treatment of osteocarcinoma with alpha-1—antitrypsin or secretory leucocyte protease inhibitor
WO2003060466A3 (fr) * 2001-12-21 2004-02-12 Immunochemistry Technologies L Marquage d'affinite des serines proteases dans la detection simultanee de plusieurs taux d'activite des serines proteases
US8633305B2 (en) 2003-08-26 2014-01-21 Leland Shapiro Compositions of, and methods for, alpha-1 anti trypsin Fc fusion molecules
US10913790B2 (en) 2003-08-26 2021-02-09 The Regents Of The University Of Colorado, A Body Corporate Compositions of, and methods for, alpha-1 anti trypsin Fc fusion molecules
US7850970B2 (en) 2003-08-26 2010-12-14 The Regents Of The University Of Colorado Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections
US9695229B2 (en) 2003-08-26 2017-07-04 The Regents Of The University Of Colorado, A Body Corporate Compositions of, and methods for, alpha-1 antitrypsin Fc fusion molecules
US9499606B2 (en) 2003-08-26 2016-11-22 The Regents Of The University Of Colorado, A Body Corporate Compositions of, and methods for, alpha-1 anti trypsin Fc fusion molecules
EP1697331A4 (fr) * 2003-12-19 2010-08-04 Merck Sharp & Dohme Inhibiteurs de kinesines mitotiques
WO2005112989A1 (fr) * 2004-05-19 2005-12-01 Imperial College Innovations Limited Inhibiteurs de proteases et leurs applications therapeutiques
US9884096B2 (en) 2005-06-07 2018-02-06 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods related to graft versus host disease and treatments thereof
WO2006133403A3 (fr) * 2005-06-07 2007-05-03 Univ Colorado Inhibiteurs de l'activite serine protease et leur utilisation dans des procedes et compositions pour le traitement du rejet du greffon et la promotion de la survie du greffon
US20120045417A1 (en) * 2005-06-07 2012-02-23 Lewis Eli C Methods and compositions for islet cell preservation
US9457070B2 (en) 2005-06-07 2016-10-04 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses of alpha 1-antitrypsin for early intervention in bone marrow transplantation and treatment of graft versus host disease
US20120045460A1 (en) * 2005-06-07 2012-02-23 Lewis Eli C Methods and compositions for treatment of graft rejection and promotion of graft survival
US8431526B2 (en) 2006-10-27 2013-04-30 E. I. Du Pont De Nemours And Company Compositions and methods for prion decontamination
US8034766B2 (en) 2006-10-27 2011-10-11 E I Du Pont De Nemours And Company Compositions and methods for prion decontamination
EP2330896A4 (fr) * 2008-09-10 2012-11-28 Univ Ben Gurion Activité antinécrotique d'alpha 1-antitrypsine
US20110237496A1 (en) * 2008-09-10 2011-09-29 Ilana Nathan Antinecrotic activity of alpha 1-antitrypsin
US20170209555A1 (en) * 2010-03-04 2017-07-27 The Regents Of The University Of Colorado, A Body Corporate Compositions and Methods for Modulating Cardiac Conditions
US9522179B2 (en) * 2010-03-04 2016-12-20 Virginia Commonwealth University Compositions and methods for modulating cardiac conditions
US20130195859A1 (en) * 2010-03-04 2013-08-01 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods for modulating cardiac conditions
US9938353B2 (en) 2011-06-24 2018-04-10 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses for alpha-1 antitrypsin fusion molecules
US12030958B2 (en) 2011-06-24 2024-07-09 The Regents Of The University Of Colorado Compositions and methods of use of alpha-1 antitrypsin fusion polypeptides
US10478508B2 (en) 2012-01-10 2019-11-19 The Regents Of The University Of Colorado, A Body Corporate Compositions, methods and uses for alpha-1 antitrypsin fusion molecules
CN107847550A (zh) * 2015-04-16 2018-03-27 首创生物药品发展有限公司 用于脑血管疾病的治疗肽
JP2018516273A (ja) * 2015-04-16 2018-06-21 プライム・バイオ‐ドラッグ・ディヴェロップメント・リミテッドＰｒｉｍｅ Ｂｉｏ‐Ｄｒｕｇ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 脳血管疾患用治療ペプチド
EP3283095A4 (fr) * 2015-04-16 2018-12-05 Prime Bio-Drug Development Limited Peptides thérapeutiques pour maladies cérébrovasculaires
CN107847550B (zh) * 2015-04-16 2021-07-30 首创生物药品发展有限公司 用于脑血管疾病的治疗肽
JP2020063311A (ja) * 2020-01-31 2020-04-23 プライム・バイオ‐ドラッグ・ディヴェロップメント・リミテッドＰｒｉｍｅ Ｂｉｏ‐Ｄｒｕｇ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 脳血管疾患用治療ペプチド

Also Published As

Publication number Publication date
US7704958B1 (en) 2010-04-27
US20110319330A1 (en) 2011-12-29
US20080261868A1 (en) 2008-10-23
US20120040913A1 (en) 2012-02-16
AU3731400A (en) 2000-09-21
WO2000051624A3 (fr) 2000-12-28
US8071551B2 (en) 2011-12-06

Similar Documents

Publication Publication Date Title
US8071551B2 (en) Methods and compositions for treating diabetes
Meriin et al. Role of molecular chaperones in neurodegenerative disorders
Powell The ubiquitin-proteasome system in cardiac physiology and pathology
US6867186B2 (en) Cell-permeable protein inhibitors of calpain
US8722626B2 (en) Method for controlling fibrosis and other pathological deposits in tissues comprising administering a GHRP-6 composition
DE19834591A1 (de) Verfahren zur Steigerung des Blutglukosespiegels in Säugern
US9522179B2 (en) Compositions and methods for modulating cardiac conditions
CA2138124A1 (fr) Utilisation d'inhibiteurs de la calpaine pour inhiber et traiter des affections medicales associees a une augmentation de l'activite de la calpaine
US20050222387A1 (en) Smac-peptides as therapeutics against cancer and autoimmune diseases
CN107106637A (zh) 用于疾病预防和治疗的方法和组合物
AU2016255021B2 (en) Short synthetic peptide for treating diseases and/or conditions related to angiogenesis
WO2007088099A2 (fr) Composes servant à traiter une ischémie et une neurodégénération
US20030133927A1 (en) Conjugates useful in the treatment of prostate cancer
US7374898B2 (en) Peptide inhibitors against seprase
KR102084341B1 (ko) 짧은 합성 펩티드 및 그의 용도
EP2340030B1 (fr) Procédés, systèmes et compositions pour inhiber les calpaïnes
US20070015708A1 (en) Methods and compositions for inhibiting tumor growth and angiogenesis
EP1354952A1 (fr) Peptides dérivés de Smac, comme agents thérapeutiques contre le cancer et les maladies autoimmunes
JP6326232B2 (ja) 関節症の処置のためのアミノスタチン誘導体
US20150299264A1 (en) Inhibition of cardiac fibrosis in myocardial infarction
US20060074020A1 (en) Inhibition of angiogenesis by neutrophil alpha-defensins
CN118829440A (zh) 用于治疗tau蛋白病的小分子肽模拟物
WO2006054773A1 (fr) Activation de la caspase lors de l'etape de division cellulaire des cellules cancereuses et utilisation de l’inibiteur de la caspase dans un agent anticancereux et autres

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase